The long-term objective of the research plan is to delineate cellular and molecular mechanisms of brain damage caused by stroke and other cerebrovascular disorders and, thereby, to contribute to the development of preventive and therapeutic measures against these important diseases. Although much information has accumulated on the pathophysiology and neurochemical pathology of ischemic disorders the mechanisms causing neuronal necrosis and tissue infarction remain largely undefined. It has been shown, though, that the final brain damage does not only depend on the density and duration of the ischemia but also on systemic and local factors including changes in plasma hormones and release of local neurotransmitters/neuromodulators. The present project is based on findings showing that preischemic hyperglycemia and/or increased glucose delivery during ischemia cause exaggerated brain damage characterized by postischemic seizures, edema, and infarction. It has been generally assumed, but never clearly shown, that brain damage is exaggerated because increased glucose availability enhances the cellular lactic acidosis. The research plan seeks to provide answers to three main questions. First, what is the role played by the systemic consequences of hyperglycemia and ischemic stress, notably by the changes in plasma concentrations of catecholamines, corticosterone, insulin, and glucagon? Second, how do postischemic seizures arise and what is their importance in aggravating ischemic brain damage? Third, how is the density of damage related to the severity of extra- and intracellular acidosis and by what mechanisms does acidosis cause cell injury? Plasma glucose concentrations will be systematically varied in anesthetized rats subjected to transient ischemia of known density and duration, tissue acid-base changes estimated, changes in plasma hormones and neurochemical variables assessed, and the tissue damage following long-term recovery estimated by quantitative histopathology. In other experiments, the modulating influence of changes in plasma hormones will be explored. The hypothesis will be tested if the postischemic seizures arise because ischemic acidosis damages inhibitory, GABA-ergic cells and systems, including that gated in the substantia nigra. A second hypothesis to be tested is one predicting that acidosis leads to exaggerated brain damage by causing delocalization of protein-bound iron and enhanced production of free radicals, with an ensuing peroxidative damage to cell membranes.